Disorders of decision-making are a prominent feature of the "dysexecutive syndrome" seen in substance addiction, as reflected by the persistent use of substances in the face of rising consequences, and the frequent denial and unawareness of an addiction problem. The long-term goal of this project is to understand the neurobiological mechanisms underlying this "myopia" for the future in substance addicts. In the current funding period we tested the hypothesis that substance addicts suffer from a decision-making impairment akin to that seen with patients with bilateral lesions of the ventromedial prefrontal (VM) cortex. We confirmed that substance addicts exhibit a pattern of behavioral and physiological results characteristic of a VM cortex dysfunction. However, lesions in other neural regions, including the insular/SII, SI cortices, the amygdala, the striatum and anterior cingulate also interfere with the processing of various aspects of emotion related signals ("somatic markers") that normally facilitate the process of making advantageous choices. This suggests that these several regions are part of a neural system involved in decision-making. Our findings during the current funding period suggest that the decision-making deficit in substance addicts may not be restricted to the VM cortex, but arises from a dysfunction that involves other components of the decision-making system. Guided by these results, the new studies we propose aim at 1) Assessing the contribution of deficits in mechanisms of working memory and response inhibition to the decision-making impairment in substance addicts. 2) Uncovering deficits responsible for the decision-making impairment in substance addicts due to dysfunction in anatomical systems outside the VM cortex. 3) Understanding how the experience of negative (e.g., sad or angry) emotions interact with mechanisms of decision-making, thereby precipitating lapse in judgment that facilitates the tendency of substance addicts to sustain substance use or to relapse. The new studies call for the testing of several hypotheses in cognitive and physiological experiments that have been developed and tested with patients with focal brain lesions. The results will contribute to 1) understanding the mechanisms underlying the "myopia" for the future, which may be one of the principle mechanisms underlying the transition from casual substance taking to compulsive and uncontrollable behavior. 2) The results will also further our understanding of how emotions and stress allow the emotional impact of immediate reward to dominate behavior, thereby precipitating relapse. 3) The results will also contribute to advancing one more step our understanding of the characteristics that predict the individual's vulnerability to becoming an addict and 4) the future development of behavioral and pharmacological management strategies of substance addiction.